Increase in Bcl-2 level promoted by CD40 ligation correlates with inhibition of B cell apoptosis induced by vacuolar type H(+)-ATPase inhibitor.
We have previously demonstrated that cell death of WEHI-231 cells induced by specific inhibitors of vacuolar type H(+)-ATPase (V-ATPase) occurs through apoptosis. CD40 is involved in regulating activation, differentiation, and apoptosis of B cells. Here we show that the CD40 ligation rescues WEHI-231 cells from apoptotic cell death induced by a specific V-ATPase inhibitor, concanamycin A. CD40 signaling with anti-CD40 antibody resulted in the induction of Bcl-2 and Bcl-XL proteins in WEHI-231 cells. Constitutive expression of Bcl-2 but not Bcl-XL inhibited concanamycin A-induced apoptosis. These findings suggest that the expression of Bcl-2 mediated through CD40 signaling rescues the apoptotic cell death induced by blockade of V-ATPase. Interestingly, the acidification of intracellular acidic compartments was completely inhibited when WEHI-231 cells were cultured with concanamycin A, even in the presence of anti-CD40 antibody. In addition, apoptosis in WEHI-231 cells induced by concanamycin A was strongly suppressed when cultured with imidazole, a cell-permeable base, suggesting that apoptosis induced by concanamycin A is preceded by intraacidification.
Akifusa
S
S
Department of Oral Science, National Institute of Infectious Diseases, Tokyo, Japan.
Ohguchi
M
M
Koseki
T
T
Nara
K
K
Semba
I
I
Yamato
K
K
Okahashi
N
N
Merino
R
R
Núñez
G
G
Hanada
N
N
Takehara
T
T
Nishihara
T
T
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001402:B-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D019013:CD40 Antigens / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016393:Lymphoma, B-Cell; D018942:Macrolides; D051379:Mice; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis*; D006180:Proton-Translocating ATPases / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D025262:Vacuolar Proton-Translocating ATPases; D051020:bcl-X Protein
D000900:Anti-Bacterial Agents; C494812:Bcl2l1 protein, mouse; D019013:CD40 Antigens; D004791:Enzyme Inhibitors; D018942:Macrolides; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; C036978:concanamycin A; D025262:Vacuolar Proton-Translocating ATPases; D006180:Proton-Translocating ATPases